Stress is a widespread condition, and is characterized by an over abundance of glucocorticoid activity. Damaging effects of glucocoroticoid overload are evident in many organs including the reproductive system. In the brain, stress-levels of glucocorticoid accelerate hippocampal aging process. One sign of this acceleration is neurodegeneration. This finding has led to the more general proposal that stress accelerates the aging process in other tissues and organs of the body, including the male reproductive system. Stress and aging appear to have inhibitory effects on Leydig cells, which are the primary source of the steroid hormone testosterone. Stress-mediated increases in glucocorticoid levels inhibit steroidogenic enzyme expression resulting in decreased rates of testosterone secretion, following a pattern that is similar to the normal process of Leydig cell aging. We hypothesize that old Leydig, cells are more susceptible to the inhibitory effects of glucocorticoid due to declines in glucocorticoid metabolism by the 11 P -hydroxysteroid dehydrogenase enzyme (11 P -HSD), and chronic stress-mediated increases in glucocorticoid levels may accelerate Leydig cell aging. The lengths of the telomeres of chromosomes shorten as all cells age. Chronic stress has been shown to increase the generation of reactive oxygen species (ROS) in tissues, resulting in a lower telomerase activity, and shorter telomeres. In the present application, the following three Specific Aims will be investigated. 1) We will define age-related changes in glucocorticoid activity and their consequences for testis function. We will test the hypothesis that levels of glucocorticoid activity in the male reproductive system increase during aging by evaluation of the levels of serum glucocorticoid, Leydig cell 110 -HSD enzyme activity and glucocorticoid receptor (GR) numbers. 2) We will test the hypothesis that chronic stress accelerates the degenerative changes associated with Leydig cell aging. This will be approached by observation of Leydig cell aging after a regimen of one-hour of stress over the course of twenty days. 3) Finally, we will measure ROS levels and telomerase activity in Leydig cells after stress and ask whether telomeres are shortened as a result of chronic stress. Based on results shown in other tissues, we expect that stressed-induced declines in Leydig cell telomere length will become established as an underlying event of male reproductive aging. [unreadable] [unreadable] [unreadable]